Transcriptional changes of BDNF and clock genes in the rat prefrontal cortex following acute agomelatine administration

Purpose: Depression is a complex disorder characterized by an array of changes affecting neurotransmitters, hormones as well as proteins important for neuronal resilience. While synaptic events represent the first step in the action of antidepressant drugs, the investigation of downstream changes involving signalling and transcriptional mechanisms allow the characterization of targets that may contribute to functional changes in selected brain regions with relevant implications for the clinical outcome. Agomelatine is a new antidepressant with melatonergic MT1/2 receptor agonist and 5-HT2C receptor antagonist properties with antidepressant activity in preclinical models as well as in Major Depressive Disorders [1]. The aim of this study was to investigate the time course of changes produced by acute treatment with agomelatine on the expression of the neurotrophin Brain-Derived Neurotrophic Factor (BDNF), as well as the relative contribution of melatonergic and 5-HT2C receptors in the actions of agomelatine. Moreover, we investigated if the potential BDNF mRNA changes induced by agomelatine could result, at least in part, from alterations on different clock genes (PER 1 and 2, CRY 1 and 2, CLOCK) expression. Methods: Male Sprague-Dawley rats were given a single in- jection of agomelatine (40mg/kg i.p.) or vehicle and BDNF mRNA expression was analyzed 1, 7 or 16h after. To evaluate the contribution of MT1/2 and 5HT2C receptors, rats were acutely treated with melatonin (40mg/kg i.p.), the 5HT2C antagonist S32006 (10 mg/kg i.p.) or the MT1/2 antagonist S22153 (20 mg/kg i.p.) in the presence of agomelatine or vehicle and killed 16 h after. PER 1 and 2, CRY 1 and 2 and CLOCK mRNA expression was assessed 7 and 16 h after agomelatine and vehicle treatment. Results: BDNF expression was significantly increased 16h after acute agomelatine administration, an effect that follows a specific temporal profile, is limited to the prefrontal cortex and it is due to changes of specific neurotrophin transcripts, including exon I, III and IV. Moreover, the acute up-regulation of BDNF mRNA levels appears to be the result of a synergistic effect between the melatonergic properties of agomelatine as MT1/MT2 agonist and its serotonergic 5-HT2C antagonism, since either melatonin or the 5-HT2C antagonist S32006 does not mimic the effects of agomelatine and pretreatment with the MT1/2 antagonist S22153 prevented the BDNF up regulation induced by agomelatine. We also found that acute agomelatine produced a significant increase of some clock genes in the rat prefrontal cortex, including PER 1, CRY 1 and CRY 2. Interestingly, most of these changes were anticipated with respect to what observed for BDNF, since they were evident at 7 h post treatment. Conclusions: Taken together, these data provide evidence that acute agomelatine treatment modulates the expression of BDNF in the rat prefrontal cortex through a functional interaction between melatonergic MT1/MT2 and 5-HT2C receptors. Since such effect appears to originate from changes in the circadian variation of BDNF expression, we suggest that agomelatine may exert at least part of its modulatory activity through the rapid regulation of several clock genes. References [1] Goodwin, G.M., Emsley R, Rembry S, Rouillon F (2009) Agomelatine prevents relapse in patients with major depressive disorder without ev- idence of a discontinuation syndrome: a 24-week randomized, double- blind, placebo-controlled trial. J Clin Psychiatry, 70:8, 1128−37.